Head circumference and height abnormalities in autism revisited: the role of pre- and perinatal risk factors

Pre/perinatal risk factors and body growth abnormalities have been studied frequently as early risk markers in autism spectrum disorder (ASD), yet their interrelatedness in ASD has received very little research attention. This is surprising, given that pre/perinatal risk factors can have a substantial impact on growth trajectories in the first years of life. We aimed to determine which pre/perinatal factors were more prevalent in ASD children and if these factors differentially influenced body growth in ASD and control children. A total of 96 ASD and 163 control children matched for gender participated. Data of growth of head size and body length during the first 13 months of life were collected. Data on pre/perinatal risk factors were retrospectively collected through standardized questionnaires. Results indicated that after matching for SES, prematurity/low birth weight and being first born were more prevalent in the ASD versus the control group. In addition, with increasing age children with ASD tended to have a proportionally smaller head circumference compared to their height. However, the effect of prematurity/low birth weight on head growth corrected for height was significantly different in ASD and control children: premature/low birth weight control children showed a disproportionate larger head circumference in relation to height during their first year of life, whereas this effect was absent in premature/low birth weight ASD children. This may suggest that the etiology of abnormal growth is potentially different in ASD and control children: where abnormal growth in control children is related to suboptimal conditions in the uterus, abnormal growth in ASD may be more strongly related to the causal factors that also increase the risk for ASD. However, prospective studies measuring growth and ASD characteristics in both premature/low birth weight and a terme children are necessary to support this conclusion.     

Genetic and perinatal determinants of structural brain deficits in schizophrenia

Using a subsample from the Copenhagen schizophrenia high-risk project, we examined the contributions of schizophrenic genetic liability and perinatal complications to computed tomographic (CT) measurements of ventricular enlargement and cortical and cerebellar abnormalities. A factor analysis of six CT measurements yielded two significant factors. One factor reflected multisite neural deficits as evidenced by abnormality of the cerebellar vermis and widening of the sylvian and interhemispheric fissures and cortical sulci. The other factor reflected periventricular damage as evidenced by enlargement of the third and lateral ventricles. Because all of the subjects had schizophrenic mothers, the major source of genetic variation is contributed by the diagnostic status of their fathers. In a stepwise multiple-regression analysis, it was determined that the multisite neural deficits factor was significantly related to genetic risk for schizophrenia (as measured by schizophrenia spectrum illness in the subjects' fathers) but was unrelated to pregnancy or delivery complications or to weight at birth. Periventricular damage was highly and significantly correlated with the number of complications suffered at delivery, but only among subjects with an elevated genetic risk. Although limited by a small sample size, these results suggest that the two types of CT abnormalities in schizophrenia may reflect partially independent processes based on different combinations of genetic and perinatal influences.     

Vascular endothelial growth factor in neonates with perinatal asphyxia

Background: Vascular endothelial growth factor (VEGF) is a polypeptide growth factor that is activated by tissue hypoxia. The role of VEGF in perinatal asphyxia in human neonates is yet to be clarified. In infants who develop moderate to severe acute hypoxic ischemic encephalopathy (HIE) it is crucial to clearly understand physiologic and biochemical changes that accompany HIE before a novel treatment can be developed. Objectives: To assess VEGF in cord blood of infants suffering from perinatal asphyxia, and to determine whether an association exists between increased concentrations of VEGF and the risk for development of encephalopathy. Study design: We prospectively studied 40 full term infants; of them 20 infants suffered from perinatal asphyxia, and 20 control infants of comparable age and sex. We obtained cord blood samples from all subjects immediately after delivery. Neurological examination and grading of HIE were performed during the first day of life. Results: Birth weight, gestational age and gender did not differ between the control (n = 20) and asphyxia (n = 20) groups. Within the asphyxia group four infants developed HIE; one with severe encephalopathy who died shortly after birth, while the other three infants had moderate HIE. Concentrations of VEGF were increased in infants with asphyxia when compared to controls (P  0.001). Within the asphyxia group, infants with HIE had significantly increased concentrations of VEGF when compared to non-HIE asphyxiated infants (P = 0.008). In the logistic regression model, VEGF inversely correlated with pH and PO₂ in cord blood, and Apgar scores at 1 min, while it did not associate with gestational age and birth weight. Conclusions: This study indicates that VEGF is increased in cord blood of neonates following birth asphyxia, and that VEGF is specifically most increased in infants who later developed encephalopathy. Further studies are required to determine the role of VEGF in brain insult. Such studies will help determine whether a therapeutic role for VEGF or VEGF inhibitors can exist for HIE infants.     

Prenatal, perinatal, and postnatal risk factors in obsessive-compulsive disorder.

BACKGROUND: The etiology of obsessive-compulsive disorder (OCD) remains unknown, although it is thought to involve an interaction of genetic and environmental factors. This study aimed to identify prenatal, perinatal, and postnatal risk factors in OCD. METHODS: We compared retrospectively 68 OCD patients to 70 control subjects based on responses given on a standardized questionnaire. The questionnaire was designed to evaluate environmental factors, with a special focus on gestation, labor, birth, and early infancy aspects. RESULTS: The group of OCD patients had risk factors with greater frequency than the control group. Notable among the significant findings (p < or = 0.001) were edema of the hands, feet, or face and excessive weight gain during gestation; hyperemesis gravidarum; prolonged labor; preterm birth; and jaundice. When socioeconomic class was used as a covariable in the logistic regression analysis, prolonged labor and edema during pregnancy remained statistically significant. CONCLUSIONS: Some early risk factors may be associated with the expression of OCD later in life such as edema during pregnancy and prolonged labor. If our findings are confirmed in future studies, greater attention should be given to such factors in predisposed individuals, especially in prenatal care and delivery.     

The black box of perinatal ischemic stroke pathogenesis

An improved understanding of perinatal stroke epidemiology, classification, neuroimaging, and outcomes has emerged in recent years. Despite this, little is known regarding the pathophysiological mechanisms responsible for most cases. A multitude of possible associations and putative risk factors have been reported, but most lack definitive empirical evidence supporting primary causation. These include obstetrical and maternal factors, perinatal conditions, infectious diseases, prothrombotic abnormalities, cardiac disorders, medications, and many others. The bulk of evidence is weak, dominated by case reports and retrospective case series. Findings from the small number of case-control and cohort studies that exist are limited by heterogeneous populations and methodologies. The single largest barrier to ultimately understanding and potentially improving outcomes from this common and disabling condition is the lack of comprehensive, fully powered risk factor studies required to definitively describe perinatal stroke pathogenesis. This review summarizes current evidence and suggests future directions for research.     

Prenatal cord clamping in newborn Macaca nemestrina: a model of perinatal asphyxia

Our objective was to establish a nonhuman primate model of perinatal asphyxia appropriate for preclinical evaluation of neuroprotective treatment strategies under conditions that closely resemble human neonatal emergencies, and to begin testing the safety and efficacy of erythropoietin neuroprotective treatment. Prior to delivery by hysterotomy, the umbilical cords of near term Macaca nemestrina (n = 8) were clamped for times ranging between 12 and 15 min. Animals received erythropoietin (5,000 U/kg/dose x 2 i.v., n = 3), or vehicle (n = 5) after resuscitation. We assessed physiologic parameters, continuous electroencephalogram, magnetic resonance imaging/spectroscopy, safety parameters and behavior. Animals were euthanized at 4 months of age. Mean birth weight was 507 +/- 62 g. Initial arterial pH ranged from 6.75 to 7.12, with base deficits of 17-25 mEq. Animals were flaccid at birth, with attenuated electroencephalograms, and seizures occurred in 3 of 8 animals. We demonstrated magnetic resonance imaging/spectroscopy changes consistent with hypoxia (elevated lactate levels were present in some animals), significant motor and behavioral abnormalities (particularly with 15 min of cord clamping), and evidence of gliosis at the time of death. We have established a reproducible model of moderate to severe perinatal hypoxic-ischemic injury in M. nemestrina newborns. This model, which combines structural, biochemical, and behavioral assessments over time can be used to assess the safety and efficacy of neuroprotective strategies.     

Prenatal and Perinatal Risk Factors for Autism in China

We conducted a case–control study using 190 Han children with and without autism to investigate prenatal and perinatal risk factors for autism in China. Cases were recruited through public special education schools and controls from regular public schools in the same region (Tianjin), with frequency matching on sex and birth year. Unadjusted analyses identified seven prenatal and seven perinatal risk factors significantly associated with autism. In the adjusted analysis, nine risk factors showed significant association with autism: maternal second-hand smoke exposure, maternal chronic or acute medical conditions unrelated to pregnancy, maternal unhappy emotional state, gestational complications, edema, abnormal gestational age (<35 or >42 weeks), nuchal cord, gravidity >1, and advanced paternal age at delivery (>30 year-old).     

Parkinson's disease and risk of mortality: meta‐analysis and systematic review

To evaluate the existing prospective observational studies on the morality risk among Parkinson's disease (PD) patients and determine the overall risk ratio (RR) of mortality by conducting a meta‐analysis and systematic review. Original articles published in English were searched in PubMed and Embase databases prior to March 2013. Only prospective observational studies providing adjusted risk estimates related to PD and future mortality were considered eligible. Pooled adjusted RR and 95% confidence interval (CI) were computed either by fixed‐effects models or by random‐effects models. Eight studies with 72,833 participants were identified and analysed. In the pooled analyses, patients with PD had a greater risk of all‐cause mortality (RR = 2.22; 95% CI: 1.78–2.77). Subgroup analyses based on the design, gender, follow‐up duration and sample size showed that a consistent positive association between PD and the mortality risk in each subgroup. However, no statistical significance was found for the baseline age <65 years (RR = 1.42; 95% CI: 0.72–2.77). PD patients with dementia had particularly high mortality risks (RR = 3.78; 95% CI: 2.06–6.92). This meta‐analysis indicated that among patients with PD, the all‐cause mortality increased by 2.22‐fold compared with the general population. PD patients with dementia particularly had higher risks of mortality.     

The retrospective measurement of prenatal and perinatal events: accuracy of maternal recall

Adverse obstetric events have been implicated as risk factors for schizophrenia. Many studies have relied on retrospective recall of these events, given typical adult onset of schizophrenia, when most studies ascertain their samples. The goal of this study was to assess the validity of an interview for the long-term recall of prenatal and perinatal events. Ninety-six women from the Providence and Boston cohorts of the National Collaborative Perinatal Project were administered a brief structured telephone interview regarding their recall of pregnancy-related events that had occurred 22 years or more prior to interview. Women accurately reported major medical events such as cesarean section, breech delivery, and multiple birth (kappa=1) and demographic items, such as age at birth and parity. Medical interventions and major medical conditions such as placental (kappa=-0.01) and cord (kappa=-0.10) difficulties were not accurately reported. Estimated birthweight, low birthweight, and length of gestation were recalled with reasonable accuracy. Women who completed high school generally recalled events more accurately than those who did not. It is therefore important to attend to the sources of information, the mode of interviewing, the specific type of event, and sociodemographic characteristics of the informant to improve the accuracy of retrospective data on obstetric events, and to increase the validity of findings relating these to the onset of schizophrenia.     

Association between indicators of perinatal asphyxia and adverse outcome in the term infant: a methodological review

There are conflicting opinions about the significance of 5 perinatal findings felt to be indicators of asphyxia (meconium staining of the amniotic fluid, abnormal fetal heart rate patterns, acidotic fetal scalp blood gases, low Apgar scores, and acidotic cord blood gases). A review of the literature was undertaken to determine the strength of association of each of these findings with adverse outcomes. Although all studies contained methodological problems, these indicators were found to have strong associations with one or more adverse outcomes such as perinatal death, low Apgar scores or cerebral palsy. The strength of the association (relative risk) was found to vary inversely with the prevalence of the outcome.     

Paediatric arterial ischaemic stroke: functional outcome and risk factors

Aim To study functional outcome in children aged 1 month to 18 years after paediatric arterial ischaemic stroke (PAIS) and to identify risk factors influencing their quality of life. Method In a consecutive series of 76 children (35 males 41 females, median age at diagnosis 2y 6mo, range 1mo–17y 2mo; median length of follow‐up 2y 4mo, range [7mo–10y 6mo]) with PAIS diagnosed at the Erasmus Medical Centre Sophia Children's Hospital between 1997 and 2006, we collected clinical, biochemical, and radiological data prospectively. In 66 children surviving at least 1 year after PAIS, functional outcome could be evaluated with the World Health Organization’s International Classification of Impairments, Disabilities and Handicaps. Results Significant risk factors at presentation for a poor neurological outcome were young age, infarction in the right middle cerebral artery territory, and fever at presentation. Fifty‐four % of children had severe neurological impairments at 12 months after PAIS, and at last follow‐up more than half needed remedial teaching, special education, or institutionalization. Health‐related quality of life (HRQOL) questionnaires showed a significantly lower HRQOL in all age groups. Children with a longer follow‐up had a lower HRQOL in the cognitive functioning domain. Interpretation Our study shows significant morbidity and mortality and a reduced HRQOL after PAIS depending on age, fever at presentation, and infarction in the right middle cerebral artery territory.     

Periodontal disease and stroke: a meta‐analysis of cohort studies

This review aimed to determine the association between periodontal disease and stroke incidence by a meta‐analysis of cohort studies. Cohort studies that evaluated the incidence of stroke (fatal or non‐fatal, ischaemic or haemorrhagic) and baseline periodontal status and calculated relative risk values were included. The quality of the included studies was assessed using an evaluation grid. The analyses were conducted separately for three outcomes: periodontitis, gingivitis and loss of teeth. Adjusted values of relative risk or of hazard ratio were used to assess risk values in each study. Random effects meta‐analyses were conducted when data could be pooled. From the 743 references retrieved, only nine cohort studies were suitable for inclusion in this review. Quality scores of the studies varied greatly. Three prospective studies, which used reliable indicators of periodontal disease, obtained the highest scores. Conversely, three studies that used a subjective evaluation of stroke incidence or diagnosed stroke without imaging obtained the lowest score. The results of the meta‐analyses varied depending on the outcome considered and the type of stroke. The risk of stroke was significantly increased by the presence of periodontitis [relative risk 1.63 (1.25, 2.00)]. Tooth loss was also a risk factor for stroke [relative risk 1.39 (1.13, 1.65)]. The risk of stroke did not vary significantly with the presence of gingivitis. This review shows that periodontitis and tooth loss are associated with the occurrence of stroke.     

Risk factors for intensive care unit‐acquired weakness: A systematic review and meta‐analysis

Intensive care unit‐acquired weakness (ICUAW) occurs frequently in the context of critical illness without alternative plausible cause and specific treatment options, and it is important to identify and summarize the independent risk factors for ICUAW. PubMed, Embase, Central, China Biological Medicine, China National Knowledge Infrastructure, VIP and Wanfang databases were searched from database inception until 10 July 2017. Prospective cohort studies on adult ICU patients who were diagnosed with ICUAW using either clinical or electrophysiological criteria were selected. Meta‐analysis was performed using Stata version 12.0. The results were analysed using odds ratios (OR) and 95% confidence intervals (CI). Data were pooled using a random‐effects model, and heterogeneity was assessed using the I² statistic. Qualitative analysis and systematic review were used for risk factors that were deemed inappropriate to combine. Fourteen prospective cohort studies were included in this review. The meta‐analysis showed that Acute Physiology and Chronic Health Evaluation II score (OR, 1.05; 95%CI, 1.01‐1.10), neuromuscular blocking agents (OR, 2.03; 95%CI, 1.22‐3.40) and aminoglycosides (OR, 2.27; 95%CI, 1.07‐4.81) were found to be significantly associated with ICUAW. Other risk factors, including female, multiple organ failure, systemic inflammatory response syndrome, sepsis, electrolyte disturbances, hyperglycaemia, hyperosmolarity, high lactate level, duration of mechanical ventilation, parenteral nutrition and use of norepinephrine, were statistically significant on multivariable analysis in each single studies. This review provides a number of independent risk factors for ICUAW, which should be guided for early prediction and prevention of the disorder.     

Placental passage of antiepileptic drugs at delivery and neonatal outcomes

Children of women treated with antiepileptic drugs (AEDs) are at increased risk of adverse outcomes detectable in the neonatal period, which may be associated with the amount of AEDs in the fetal circulation. Placental passage of AEDs can be measured by calculating the ratio of umbilical cord to maternal AED concentrations collected at delivery. The aims of this study were to determine the umbilical cord concentrations and umbilical‐to‐maternal ratios for AEDs, and whether higher cord concentrations are associated with increased risk of neonatal complications. AED cord and maternal blood concentrations from 70 mother–newborn dyads and neonatal complications were recorded. Logistic regressions were performed to determine the association between AED concentrations and complications. Mean umbilical‐to‐maternal ratios for total concentrations ranged from 0.79 for carbamazepine to 1.20 for valproic acid, and mean umbilical‐to‐maternal ratios for free concentrations ranged from 0.86 for valproic acid to 1.42 for carbamazepine, indicating complete placental passage. Neither umbilical cord concentrations nor umbilical‐to‐maternal ratios were associated with adverse neonatal outcomes. Additional investigations are warranted to delineate the relationship between quantified fetal AED exposure and neonatal complications.     

Risk factors for perinatal arterial stroke: a study of 60 mother-child pairs

The objective of the present study was to examine demographic, historical, and prothrombotic risk factors in infants with perinatal arterial stroke and their mothers. Risk factors were evaluated in 60 mother-child pairs with perinatal arterial stroke. Prothrombotic factors analyzed included the DNA mutations factor V Leiden, prothrombin 20210, MTHFR C677T and A1298C; serum activity levels for protein C, protein S, and antithrombin III; serum levels of lipoprotein(a); and, in the mothers, antiphospholipid antibodies. Boys predominated, 36:24. There were four twin sets. Sixty percent were term and 22% were post-date. Ten were large for gestational age. Five mothers had abdominal trauma. Nine mothers (15%) had preeclampsia. Emergency caesarean section was performed in 17 cases (28%). Eight placental exams revealed seven with abnormalities. Seizures were the presenting sign in 70%, and 30% presented with early handedness or cerebral palsy. Prothrombotic risk factors were found in 28 of 51 mothers (55%) and 30 of 60 children (50%). Forty-one pairs (68%) had at least one abnormality in mother, child, or both. Long-term sequelae included cerebral palsy (40 of 51; 78%), cognitive impairment (35 of 51; 68%), seizures (23 of 51; 45%), and microcephaly (26 of 51; 51%). Perinatal arterial stroke is the result of multifactorial, synergistic fetal and maternal factors among which the prothrombotic factors, both fetal and maternal, appear significant.     

The prenatal,perinatal and neonatal risk factors for children's developmental coordination disorder: A population study in mainland China

We initially conducted a population-based study on developmental coordination disorder (DCD) in mainland China to explore the prenatal, perinatal and neonatal risk factors on DCD. A total of 4001 children were selected from 160 classes in 15 public nursery schools. The Movement Assessment Battery for Children-Second Edition (MABC-2) was used to assess the children's motor function. Crude and adjusted odds ratios were estimated to determine the strength of association using a multilevel logistic regression model with a random intercept. Three hundred and thirty children out of 4001 subjects met the DSM-IV criteria for DCD, and 3671 children were non-DCD. Maternal age, threatened abortion, fetal distress during labor, preterm birth, chronic lung disease and newborn pathological jaundice were related with DCD (OR = 1.72, 2.72, 9.14, 5.17, 1.43, and 2.54, respectively, each p < 0.05). Considered collectively, these risk factors may provide clues to an etiology of DCD. Additionally, the practitioners of maternity and child health care should improve the assessment and monitoring of the prenatal, perinatal and neonatal risk factors for DCD.     

Head injury and risk of Parkinson disease: A systematic review and meta‐analysis

Head trauma has been implicated in the etiopathogenesis of Parkinson's disease (PD). We performed a meta‐analysis to investigate the association between head trauma and the risk of developing PD. We included observational studies if they (1) clearly defined PD, (2) defined head trauma leading to concussion, and (3) presented odds ratios (ORs) and 95% confidence intervals (CIs) or provided data to compute these statistics. Random effect model was used to estimate the pooled, adjusted OR. Heterogeneity between studies was evaluated with the Q test and the I² statistic. We conducted a sensitivity analysis to assess the influence of each study and repeated the analysis by excluding the studies with the largest weights. We used funnel plot to assess the presence of publication bias. After reviewing more than 636 article titles, 34 articles were selected for full review. In total, 22 studies (19 case–control studies, 2 nested case–control studies, and 1 cohort study) were included in the meta‐analysis. The pooled OR for the association of PD and head trauma was 1.57 (95% CI, 1.35–1.83). The results of our meta‐analysis indicate that a history of head trauma that results in concussion is associated with a higher risk of developing PD. © 2013 Movement Disorder Society     

Prenatal and perinatal antecedents of febrile seizures

We examined prenatal and perinatal characteristics as possible risk factors for febrile seizures in a large pediatric population. Family history was among the few identified factors that made an important contribution to vulnerability to febrile seizures; however, no more than 6% of febrile seizures could be attributed to a characteristic of family history. Maternal illness, smoking history, and a few rare neonatal characteristics were associated with increases in risk. No complication of labor or delivery was an important risk factor for febrile seizures.     

Brain-stem auditory evoked potentials in children with perinatal encephalopathies.

OBJECTIVE: We sought to describe if neurological damage, in terms of brain lesions, syndrome and syndrome severity led to abnormalities in the brain-stem auditory evoked potentials (BAEPs) in order to provide a profile of children that could be used as an indicator of subsequent neurological sequelae. We analyzed the BAEPs from a group of children having prior evidence of neurological damage and determined the presence of neurological sequelae when the subjects were 3 years old. METHODS: Brain-stem auditory evoked potentials (BAEPs) were carried out in a group of 154 children with perinatal neurological damage. The children were classified with neurofunctional (clinical and EEG alterations) or organic and neurofunctional brain disease (clinical, EEG and image alteration) and were all followed from the first month of life and serially for 3 years. We used principal component analysis (PCA), clustered analysis and linear correlation to determine association between BAEPs, risk factors and future sequelae. RESULTS: Latencies of BAEPs decreased significantly with age, and the time of conduction was modified by the presence of neurological damage. All statistical analyses suggested positive and significant associations between risk factors (trophism and condition at birth), and the latencies of waves I, III and V as well as with IPL III-V (interpeak latency) and I-V. PCA showed that IPL I-III was also positively associated with condition at birth, severity of the neurological syndrome and encephalopathy. In addition, we found that the presence and type of sequela reflected changes in the latencies of the waves, as well as IPLs, primarily those of IPL I-III. CONCLUSIONS: Our results suggest that statistical methods are often needed to analyze neurological damage. The relation between BAEPs, risk factors and neurological sequelae allowed us to obtain a profile of children, which can be then used as an aid in the prognosis of children having a risk of developing neurological sequelae.